WAT ALTERATIONS IN DIABETIC MICE: ITS CONNECTION AND IMPLICATION IN AD PATHOGENESIS

Alzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences have suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses associated with white adipose tissue expansion, are risk factors for AD. Here, we hypothesize that the white adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses. We used histological stains, immunohistochemistry and biochemical means to determine changes in the white adipose tissue from WT and db/db mice. Moreover, similar techniques were used in the brain of 3xTg-AD mice that received white fat pads from WT and db/db donors to determine any changes in amyloid and tau pathology. Our study shows that recipient 3xTg-AD mice from db/db fat pads mice develop profound changes in tau pathology due to increased CDK5/p25 expression compared to 3xTg-AD mice that received fad pads from WT mice. This increment in tau level was associated with elevated levels in IL-1β and microglial activation. However, we found that Aβ levels were reduced in recipient 3xTg-AD mice from db/db fat pads compared to 3xTg- AD mice that received fad pads from WT mice. These reduction in Aβ levels were correlated with an increment in microglia phagocytic capacity. Overall, our study demonstrates a novel important crosstalk between AD and diabetes type II through white adipose cells and a differential effect on tau and Aβ pathology

Impact of white adipose tissue in AD pathology

Introduction: Alzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences has suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. In addition, novel studies has suggested that AD induces peripheral metabolic alterations, facilitating the development of diabetes. Overall, these studies suggest that there is an important two-way crosstalk between AD and peripheral metabolic disorders. Here, we seek to understand the mechanisms underlying this association and we hypothesize that the white adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses and alterations in this organ may affect both types of disorders. Methods: Here, we used histological stains, immunohistochemistry and biochemical means to determine changes in the white adipose tissue from wt and 3xTg-AD mice. Moreover, similar techniques were used in the brain of 3xTg-AD mice that received white fat pads from wt and 3xTg-AD donors to determine any changes in amyloid and tau pathology. Results: Our study shows that 3xTg-AD mice develop significant peripheral metabolic alterations which in turn affected the white adipose tissue biology. Moreover, adipose tissue transplanted from donor 3xTg-AD and wt mice into recipient 3xTg-AD mice indicate that AD associated white fat tissue induced profound AD pathology changes in recipient 3xTg-AD mice. Conclusions: Overall, our study demonstrate a novel important crosstalk between AD and peripheral metabolic disorders thought white adipose cells. A more profound understanding in these processes may turn in novel and promising therapeutic strategies for AD and metabolic illnesses.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Human amyloid seeds aggregate more efficient than seeds from old 3xtg-ad mice

Aims: Most age-associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process of template protein corruption or seeding. In fact, studies in animal models show that the injection of brain homogenates from AD patients or from aged APP-transgenic mice containing Aβ aggregates, can induce some of the neuropathological hallmarks of AD. However, it is still unknown which Aβ-misfolded species are most efficient in triggering the aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg-AD model) is more efficient to generate amyloid aggregates. Methods: We employed histological and molecular approaches to determine amyloid level, species and aggregative capacity of brain homogenates from an AD patient (stage C for amyloid, from the Alzheimer’s Disease Research Center at UCI) vs old-3xTg-AD mice (25-month-old). Such brain homogenates were injected into the hippocampus of 7-month-old 3xTg-AD mice and the mice were analyzed at 18 months of age. Results: Our findings demonstrated that amyloid seeds from the human patient have more capacity to generate Aβ plaques vs seeds from aged 3xTg-AD mice. Conclusions: These results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg-AD mice. Thus, more profound understanding these factors will provide key insight on how amyloid pathology progress in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Amyloid propagation in a sporadic model of Alzheimer disease

Most age-associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process of template protein corruption or seeding. In fact, studies in FAD-based animal models show that Aβ deposition and cerebral amyloid angiopathy may be induced by intracerebral infusion of brain extracts from AD patients or from aged APP-transgenic mice. These studies have shown that the characteristic of both the seeding agent and the host influence the pathologic signature of the Aβ seeds. In this regard, the majority of the Aβ-seeding studies have been done in APP-transgenic animal models that overproduce APP and/or Aβ. However, it remains to be elucidated whether Aβ deposition can be induced by Aβ seeds in an animal model that does not overexpress APP and produces wild type human Aβ and if these aggregates are similar to the human condition. Here, we used an innovative animal model to better understand the amyloidogenic events that occur in the sporadic form of the disease. Our model, termed hAβ-KI, expresses wild-type human Aβ under the control of the endogenous mouse APP gene. Thus, amyloid seeds from AD patients (stage C for amyloid) from the Alzheimer’s Disease Research Center (ADRC) at UCI were administered into 7-8-month-old hAβ-KI and as positive controls 3xTg-AD mice were employed. Our findings demonstrated that amyloid seeds differentially occur in 3xTg-AD and hAb-KI mice and these aggregates are developed earlier in the familial model, 3xTg-AD mice. These results suggest that multiple factors such as the seed, recipient model and time are critical factors that can modulate the amyloid pathology onset and progression. Thus, more profound understanding these factors will provide key insight on how amyloid pathology progress in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The effect of different amyloid seeds and animal hosts on amyloid propagation in Alzheimer's Disease

Abstract text: Alzheimer's Disease is a neurodegenerative proteinopathy in which recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process of template protein corruption or seeding. In fact, studies show that Aβ deposition can be induced by the intracerebral infusion of seed-containing brain homogenates, and that the characteristics of both the seeding agent and the host, influence the pathologic signature of the Aβ seeds. However, it is still unknown which Aβ-misfolded species are most efficient in triggering the aggregation process and which is the effect of amyloid seeds on different AD models. Methods: Amyloid seeds from AD patients (stage C for amyloid) from the Alzheimer’s Disease Research Center (ADRC) at UCI were administered into 7-8-month-old hAβ-KI mice and 3xTg-AD mice. Next, we intracerebrally injected brain homogenates from the human AD patient and 25mo-3xTg-AD mice into the hippocampus of 7-month-old 3xTg-AD mice, which were analyzed at 18 months of age. Results: Our findings demonstrated that amyloid deposition differentially occurs in 3xTg-AD and hAβ-KI mice, and the Aβ aggregates are developed earlier in the familial model. Moreover, the amyloid seeds from the human patient induce more aggressive amyloid pathology compared to seeds from aged 3xTg-AD mice. Conclusion: These results suggest that multiple factors such as the seed, recipient model and time are critical factors that can modulate the amyloid pathology onset and progression. Thus, more profound understanding of these factors will provide key insight on how amyloid pathology progresses in AD